The present invention relates to medical devices and methods of using same, and more particularly to devices and methods for producing bradycardia, increased systemic vascular resistance, decreased cardiac work, and increased cerebral blood flow through the autonomic nervous system in the animal or human body.
The dive reflex, also known as the dive response, is the mechanism through which the human body defends itself from hypothermia and resulting death when submerged in cold water. The reflex is most graphically illustrated by the resuscitation of children, who have been submersed in farm ponds during the winter for periods exceeding the three-minute brain-death criterion. During the dive reflex, the body, through selective vasoconstriction, isolates those tissues with extended anaerobic capability from those with relatively little anaerobic capability, such as the heart and brain. Consequently, circulation to the extremities is greatly diminished, while circulation to the brain and heart continues at generally adequate or increased levels. Additionally, the pulse-rate slows and a relatively constant blood pressure is maintained. Typically, the resulting minimum dive-reflex pulse-rate is approximately 60 to 70 percent of the quiescent rate. By shunting blood to the brain and heart, and slowing the pulse-rate, the body is able to supply the required oxygen to both the brain and the heart for extended periods of cold water submersion.
Although the dive reflex phenomenon has been known for years, there are several new triggering mechanisms for the dive reflex which have only recently been determined. Through selective anatomical immersion, it has been determined that the receptor mechanism is located in the face. See, J. Finley et al, Autonomic Pathways Responsible for Bradycardia on Facial Immersion, Journal of Applied Physiology, Volume 47(6), Pages 1218-22 (December 1979). In a 1984, Moore implied in U.S. Pat. No. 4,466,439, that the dive reflex was best triggered by isolating and stimulating the seventh cranial facial nerve (Cranial Nerve VII) based on a hypothesis that the triggering receptor was in the facial nerve which surfaces at the cheeks, forward of the ears to the nose. This has now been disproved and it has since been shown that it is the completely separate cranial nerve (fifth cranial nerve V), namely the trigeminal nerve, which possesses the receptors to activate the dive response. The trigeminal nerve surfaces over the forehead, between the eyes and down the upper part of the nose. These receptors in the skin have been isolated and have been named “cold and menthol” receptors after the stimulus known (at that time) to activate them. Particularly, it is the ophthalmic division of the trigeminal nerve which carries this reflex. Further investigations have pointed to the anterior ethmoidal nerve (surfacing on the nose) as being the most capable branch to evoke this reflex.
Stimulation of the dive response causes bradycardia, reduced cardiac work, and peripheral vasoconstriction of blood vessels. Blood is removed from the limbs and all organs except the heart and the brain allowing the mammal to conserve oxygen, and shunt blood back to the heart and brain. In humans, the mammalian dive reflex is not induced when any limbs are introduced to cold water. Notably, the greatest bradycardia effect is induced when the subject is holding one's breath (which may trigger other mechanoreceptors in the lungs) with the face submerged. This finding may be particularly helpful when utilizing the dive reflex to increase G-force tolerance of military pilots or astronauts. Protocols for the military already include “breath-hold” maneuvers to increase intra-thoracic pressure (COMBAT EDGE). Further, controversy exists over whether present technologies such as ATAGS (advanced tactical anti G suits) are of any benefit in improving G force tolerance. Like MAST trousers (now all but obsolete), ATAGS attempts to push fluid and pressure from the lower extremities into the central vascular tree in an attempt to increase systemic vascular resistance, but no increase in systemic vascular resistance can be documented. Triggering the dive reflex affords the ability to directly access the autonomic nervous system and increase the vascular resistance of every non-essential vessel throughout the body. Systemic vascular resistance increases of 25% have been noted, while increases in the cerebral blood blow in humans were seen to increase by 14%.
Interestingly, it has also been demonstrated that the spleen, in humans, contracts up to 20% during this reflex to infuse blood and increase the hematocrit up to 5%, thus further improving oxygen delivery to essential central organs. This “auto transfusion” of 5% of oxygen carrying capacity becomes critical in settings where the individual is losing blood or going into shock. Naturally, with improved hemodynamics and greater oxygen delivery, cardiac work would be expected to drop and in fact this was demonstrated by this investigator to drop by at least 11% using an external monitoring device called impedance plethysmosgraphy (Bio Z monitor).
The present approach to altering the oxygen supply/demand for the heart and brain is to use the 110-year-old technology of a sublingual nitroglycerine tablet or spray that attempts to create the same scenario through chemical means. Nitroglycerine works by a mechanism of producing nitric acid inside the vascular wall (thereby dilating it), and it requires a process of absorption of the chemical (usually through the tongue) taking at least 2 minutes and lasting only 30 minutes. Further, the intent of nitroglycerin action is to improve the oxygen supply and demand curve of the heart, a goal that is completely in accord with the actions of the dive reflex. Unfortunately, nitroglycerine has not been able to demonstrate a benefit in the setting of brain attacks (strokes and transient ischemic attacks), whereas, the dive reflex should significantly prevent or at least improve tolerance of ischemia in the central circulation of the brain based on studies which have shown up to a 14% increase in flow to the cerebrum when triggering the dive reflex in humans.
As reported in the Mar. 7, 2002 issue of Nature, McKemy, Neuhausser & Julius characterized and cloned a menthol receptor from trigeminal sensory neurons that is also activated by thermal stimuli in the cool to cold range. This cold- and menthol-sensitive receptor, CMR1, is a member of the TRP family of excitatory ion channels. They proposed that CMR1 functions as a transducer of cold stimuli in the somatosensory system. In February 2004, H-J Behrendt, et. al., published a study on the effects of 70 odorants and menthol-related substances on recombinant cold-menthol receptor TRPM8 (mTRPM8), expressed in HEK293 cells. Ten substances (linalool, geraniol, hydroxycitronellal, WS-3, WS-23, FrescolatMGA, FrescolatML, PMD38, CoolactP and Cooling Agent 10) were found to be agonists.